Abstract CT032: Trials in progress: a global phase 1/1b clinical trial evaluating exarafenib (KIN-2787), a highly selective pan-RAF inhibitor, in adult patients with BRAF-altered solid tumors and NRAS mutant melanoma
Authors: Alexander Spira, Valentina Gambardella, Shumei Kato, Cesar Batista Perez, Meredith Mckean, Maria Gonzalez Cao, Richard Kim, Chris T Chen, Antoine Italiano, Philippe Cassier, Janice Mehnert, Bartosz Chmielowski, Gerri Lee, Paul Severson, Caro Unger, Xiaowei Guan, Richard Williams, Georgina Long
Journal: Cancer Research (2023)

Abstract Background: Patients with cancers driven by BRAF Class II (C II) or C III alterations and/or NRAS mutations are unlikely to benefit from approved BRAF-targeted therapies and have few other treatment options. Exarafenib is a potentially best in class orally available pan-RAF inhibitor optimized for potency &amp; high selectivity. It has differentiated dose-dependent activity across a broad range of cell lines &amp; models driven by BRAF C I (inc. those with acquired resistance to 1st gen RAFi), C II, C III or NRAS alterations. Methods: KN-8701 (NCT04913285) is an ongoing Phase 1 dose escalation &amp; dose expansion study at 35 sites in 7 countries evaluating exarafenib monotherapy in participants (pts) with advanced solid tumors harboring oncogenic BRAF or NRAS alterations. Results: Preliminary results as of 13 Dec 2022 are reported for 52 pts (median age 63, 51.9% male) with a median of 3 prior therapies treated in 6 dose levels. Treated pts included those with solid tumors driven by BRAF C I (38.5%), C II (19.2%), C III (28.8%) alterations or melanoma pts with NRAS mutations (13.5%). Steady state exarafenib exposure (Cmax and AUC) increased dose proportionally. Pathway inhibition &amp; decreases in ctDNA were observed across BRAF classes &amp; tumor types. Dose limiting toxicities observed at the highest dose level were Grade 3 (Gr3) acneiform rash &amp; Gr3 macular rash. The maximum tolerated dose (MTD) was determined to be 300 mg bid. Treatment-related adverse events (TRAEs) (any grade) occurred in 69.2% of pts with 13.5% of pts having Gr ≥3 events. Skin AEs (any grade) were the most common TRAEs observed in 48.1% of pts with 7.7% of pts having Gr ≥ 3 skin events. GI TRAEs occurred in 19.2% pts (Gr 1-2 only), including diarrhea (1 pt, Gr 1). Reversible, asymptomatic Gr 3 increased ALT and/or increased AST AEs in 3 pts were the only non-skin Gr ≥ 3 TRAEs reported in ≥ 2 pts. At therapeutically relevant exposures, there was no cutaneous evidence of paradoxical activation. Of the 34 pts across all dose levels with at least 1 post-baseline tumor assessment, 6 pts (17.6%) had a partial response (5 confirmed at submission date) &amp; 16 pts (47.1%) had stable disease including 8 pts (23.5%) with objective tumor shrinkage (up to 20%). The 6 responders all continue exarafenib therapy (treatment duration up to 12 months) and include 3 pts with BRAF C I alteration-driven cancers (inc. 1 RAFi + MEKi pre-treated melanoma pt) and 1 pt each with BRAF C II, BRAF C III-driven &amp; NRAS-mutation driven cancers. For pts who achieved or confirmed their best response at MTD, the response rate was 33% (4/12) &amp; included responses in pts with BRAF C I, C II, C III, and NRAS mutant tumors. Conclusions: Exarafenib achieves therapeutically meaningful drug exposures and demonstrates promising tolerability &amp; clinical activity in BRAF or NRAS alteration-driven solid tumors. Pt enrollment &amp; exarafenib treatment at 300 mg bid continues. Citation Format: Alexander Spira, Valentina Gambardella, Shumei Kato, Cesar Batista Perez, Meredith Mckean, Maria Gonzalez Cao, Richard Kim, Chris T Chen, Antoine Italiano, Philippe Cassier, Janice Mehnert, Bartosz Chmielowski, Gerri Lee, Paul Severson, Caro Unger, Xiaowei Guan, Richard Williams, Georgina Long. Trials in progress: a global phase 1/1b clinical trial evaluating exarafenib (KIN-2787), a highly selective pan-RAF inhibitor, in adult patients with BRAF-altered solid tumors and NRAS mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT032.